It is known that various lipid mediators such as eicosanoid and platelet activating factor (PAF) are produced by the activity of phospholipase from cell membranes.
Lysophosphatidic acid of formula
(wherein R is acyl, alkenyl or alkyl) is a lipid which is produced in cell membranes or in blood of living organisms, and it acts as a signal transduction substance and delivers various signals into cells. Among them, L-α-LPA exists naturally And it is also known that R in the formula migrates into the hydroxy group at the 2-position.
Recently, three subtypes of LPA receptors have been identified and it is gradually proved that their various physiological activities are via these LPA receptors. These three subtypes of LPA receptor are called EDG (Endothelial differentiation gene)-2, 4 and 7, and they form EDG receptor family together with EDG-1, 3, 5, 6 and 8 (S1P1, S1P3, S1P2, S1P4, S1P5), which are sphingosine-1-phosphate receptors. EDG-2 is called LPA1 or VZG-1, too (Mol Pharmacol Dec; 58(6): 1188-96(2000)). LPA binds to EDG-2, 4 or 7 (LPA receptors) and it transmits a signal into the cells via G-protein coupled to the receptors. Gs, Gi, Gq and G12/13, etc. are known as G-proteins which can bind to the LPA receptors, and the varieties are involved with the effect mechanism of LPA. And EDG-2, 4 and 7 are distributed extensively in a body, but since different subtypes have different ways of localization, it is considered that each receptor has different roles depending on the organs. However, the kinds of receptor subtypes localized in each organ are not specified yet.
It is known that LPA is concerned with the proliferation of airway smooth muscle cells, mesangium cells and fat cells [Am. J. Physiol. Lung Cell Mol. Physiol. 2002 282(1): L91; Clin. Science 1999 96 431; J. Clin. Invest.1998 101 1431; Am. J. Physiol. (267 Cell Physiol. 36): C204, 1994]. It is also known that LPA is concerned with the activation of dendritic cells (J Immunol 2002 Oct. 15; 169(8), 4129). However, it was not revealed via which subtype of LPA receptors these effects were evoked.
In the specification of WO 01/60819, it is disclosed that a compound having an antagonistic activity against the LPA receptor inhibits the proliferation of brain tumor cells and ovarian cancer cells. However, the specification discloses only the experiment of inhibition of proliferation using cancer cells. In cancer cells, innate phenotype of differentiated cells is lost and cancer cells repeat multiplication permanently. A cultured cell line derived from normal organs has different properties from cancer cells. Therefore, the same result is not expected in the cultured cell line derived from normal organs as the result of inhibition of proliferation of cancer cells, and so these results are not to be associated easily and directly.